Sex Differences in Doxorubicin‐Induced Cardiotoxicity: Insights from Transcriptome Analysis

Male patients have a higher risk of cardiotoxicity following doxorubicin (DOX) treatment than female patients. However, how this difference occurs at the transcriptome level remains unclear, and the mechanisms underlying these differences are understudied. This study aimed to describe the transcriptional patterns of males and females after DOX treatment and explore the possible mechanisms of sexual differences in DOX‐induced cardiotoxicity. Following DOX treatment, male mice exhibit more severe heart damage than female mice. Transcriptome analysis of mice with and without DOX treatment showed that differentially expressed genes (DEGs) are significantly different between males and females. The majority of DEGs are sex‐specific, and more DEGs are identified in males than females. A number of genes, including the oxidation‐related genes Gdf15 and Rbm3, exhibited altered expression either in males or females. Some other genes, including the ferroptosis‐related gene Cd74, changed their expression levels in both sexes, but at different scales. Biochemical experiments suggested that cardiomyocyte oxidation and ferroptosis may contribute to the sexual dimorphism of DOX‐induced cardiotoxicity. In summary, this study shows that, after exposure to DOX, males and females respond differently regarding the expression of hundreds of genes, including Gdf15, Rbm3, and Cd74, possibly explaining the sexual differences in DOX‐induced cardiotoxicity. Uncovering the molecular mechanisms of sex difference in DOX (doxorubicin)‐induced cardiotoxicity is important for DOX's application in male and female patients with cancer. The results of this study show that after DOX treatment, males and females have significantly different patterns of differentially expressed gene. Genes related to oxidation and ferroptosis may contribute to the sexual difference of DOX‐induced cardiotoxicity.